In this R35, I review obstacles to cancer prevention and early detection including the needs: 1) to reconcile individual risk factors for ovarian cancer with the totality of epidemiologic evidence; 2) to find unifying explanations for risk factors common to different cancers; 3) to demonstrate that mucin tumor antigen levels are changed not only by the tumor but also by risk factors for the tumor; and 4) to be able to consider serum biomarkers in the context of the white blood count (WBC). Our research suggests ovarian cancer pathogenesis involves acute and chronic events that affect immunity related to the mucin (MUC) family of proteins, CA15.3 (MUC1) and CA125(MUC16). These line epithelial tracts and are over expressed during inflammatory, hormonal, or neoplastic events affecting these tissues. Acute events like mumps or a tubal ligation release tumor-like MUC1 and MUC16, expose them to the immune system, and create anti-MUC1 or anti-MUC16 antibodies protective against mucin-expressing ovarian cancer. Chronic events like endometriosis, repeated ovulation, and talc use in the genital area cause persistent exposure to mucins, down regulation of immunity, lower antibody levels, and increased risk for ovarian cancer. Immunity may also explain risk factors like aging, obesity, smoking, childhood infections, and reproductive factors that are common to many different cancers. We have sought to promote the idea that it is not only a cancer that can affect mucin antigen (or anti-mucin antibody) levels but also risk factors for cancer such as age, ethnicity, BMI, parity, and smoking. Associations between risk factors and mucin markers can be seen in both cancer cases and controls. A major obstacle is a paucity of datasets that allow mucin antigen (or antibody) levels to be examined in the context of the WBC count. We studied CA125, epidemiologic factors, and WBC counts at diagnosis of ovarian cancer and calculated the neutrophil-to-lymphocyte ratio (NLR), a biomarker of inflammation. Greater NLR and lower lymphocyte count was associated with higher tumor stage and grade, higher CA125, and poorer survival. NLR correlated with risk factors including Jewish ethnicity, taller height, more ovulatory cycles, family history of cancer, and talc use. To move forward, we propose to: 1) assay CA125, CA15.3, anti-CA125 and anti-CA15.3 antibodies in sera from ovarian cancer cases at diagnosis and women from national surveys, both with WBC and risk factor data; 2) develop a novel assay to quantify binding of CA125 (or CA15.3) to WBC subclasses; 3) study the functional immune effects of CA125-binding to WBCs; and 4) begin a next generation case control study that enrolls cases and benign disease controls prior to therapy and collects baseline WBC, risk factor data, and operative specimens. For three decades, I have sought to advance the prevention and early detection of ovarian cancer through epidemiologic and biomarker research and gained a broad vision inter- relating common risk factors for cancer, mucin tumor antigens, and humoral and cellular immune reactions to them. Taking this research forward expeditiously can only be accomplished by an R35 mechanism.